Armillaria mellea polysaccharides (AMPs) were obtained by ultrasonic assisted extraction (U), enzyme assisted extraction (E) and ultrasonic-enzyme assisted extraction (UE), respectively. The yield of UE-AMPs (6.32 ± 0.14%) was 1.64 times higher than that of U-AMPs (3.86 ± 0.11%) and 1.21 times higher than that of E-AMPs (5.21 ± 0.09%); meanwhile, the highest total sugar content and the lowest protein content were found in UE-AMPs. AMPs obtained from the three extraction methods had the same monosaccharide composition but in different proportions, allowing UE-AMPs to have the most potent antioxidant activity. The antidiabetic activity of UE-AMPs was investigated in streptozotocin (STZ)-induced diabetic mice. UE-AMPs, when given by gavage, greatly prevented weight loss, increased water intake, and considerably decreased blood glucose levels in diabetic mice, which were dose-dependent (P < 0.05). In addition, UE-AMPs also had a positive effect on the reduction of lipid levels in the blood, oxidative damage and liver function impairment. The pathological observation by hematoxylin-eosin staining (HE) revealed that UE-AMPs protected the organs of mice from diabetic complications (liver disease and nephropathy). Hence, our findings demonstrate that UE-AMPs are a suitable choice for improving diabetes and its complications and have great application prospects in the fields of natural medicine and functional food.